Lipid-Induced Epigenomic Changes in Human Macrophages Identify a Coronary Artery Disease-Associated Variant that Regulates PPAP2B Expression through Altered C/EBP-Beta Binding

Michael E. Reschen, Kyle J. Gaulton, Da Lin, Elizabeth J. Soilleux, Andrew J. Morris, Susan S. Smyth, Christopher A. O'Callaghan

Research output: Contribution to journalArticlepeer-review

60 Scopus citations

Abstract

Genome-wide association studies (GWAS) have identified over 40 loci that affect risk of coronary artery disease (CAD) and the causal mechanisms at the majority of loci are unknown. Recent studies have suggested that many causal GWAS variants influence disease through altered transcriptional regulation in disease-relevant cell types. We explored changes in transcriptional regulation during a key pathophysiological event in CAD, the environmental lipid-induced transformation of macrophages to lipid-laden foam cells. We used a combination of open chromatin mapping with formaldehyde-assisted isolation of regulatory elements (FAIRE-seq) and enhancer and transcription factor mapping using chromatin immuno-precipitation (ChIP-seq) in primary human macrophages before and after exposure to atherogenic oxidized low-density lipoprotein (oxLDL), with resultant foam cell formation. OxLDL-induced foam cell formation was associated with changes in a subset of open chromatin and active enhancer sites that strongly correlated with expression changes of nearby genes. OxLDL-regulated enhancers were enriched for several transcription factors including C/EBP-beta, which has no previously documented role in foam cell formation. OxLDL exposure up-regulated C/EBP-beta expression and increased genomic binding events, most prominently around genes involved in inflammatory response pathways. Variants at CAD-associated loci were significantly and specifically enriched in the subset of chromatin sites altered by oxLDL exposure, including rs72664324 in an oxLDL-induced enhancer at the PPAP2B locus. OxLDL increased C/EBP beta binding to this site and C/EBP beta binding and enhancer activity were stronger with the protective A allele of rs72664324. In addition, expression of the PPAP2B protein product LPP3 was present in foam cells in human atherosclerotic plaques and oxLDL exposure up-regulated LPP3 in macrophages resulting in increased degradation of pro-inflammatory mediators. Our results demonstrate a genetic mechanism contributing to CAD risk at the PPAP2B locus and highlight the value of studying epigenetic changes in disease processes involving pathogenic environmental stimuli.

Original languageEnglish
Article numbere1005061
JournalPLoS Genetics
Volume11
Issue number4
DOIs
StatePublished - Apr 1 2015

Bibliographical note

Publisher Copyright:
© 2015 Reschen et al.

Funding

FundersFunder number
National Institute for Health Research
National Institutes of Health (NIH)
U.S. Department of Veterans Affairs
American the American Heart Association
National Institute of General Medical SciencesP20GM103527
Wellcome Trust090532
Medical Research Council-São Paulo Research FoundationG0900747 91070
Not addedG0900747
National Center for Research ResourcesS10RR024598
U.S. Department of Veterans AffairsI01BX001984
Wellcome Trust097089/Z/11/Z, 090532/Z/09/Z
Medical Research Council-São Paulo Research FoundationG116/165

    ASJC Scopus subject areas

    • Ecology, Evolution, Behavior and Systematics
    • Molecular Biology
    • Genetics
    • Genetics(clinical)
    • Cancer Research

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